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Induced pluripotent stem cells — opportunities for disease modelling and drug discovery

Nature Reviews Drug Discovery volume 10, pages 915–929 (2011)Cite this article

Subjects

Key Points

  • Induced pluripotent stem cells (iPSCs) that are derived from patients and differentiated in vitro can provide disease-relevant cell types for drug screening.

  • Directed differentiation of iPSCs has yielded many disease-relevant cells — chiefly neurons, hepatocytes, blood cells and cardiomyocytes — but often the cells reflect embryonic stages of development, and may not faithfully reflect disease phenotypes of adult tissues.

  • Methods for deriving iPSCs are evolving, and much remains to be learned about the genetic and epigenetic stability of iPSCs and their relationships to embryonic stem cells, and how this affects the fidelity of drug screening.

  • Notwithstanding a few exceptions, disease modelling so far has focused on Mendelian disorders of high clinical penetrance and with a recognized cellular pathophysiology, such as spinal muscular atrophy, familial dysautonomia, Rett syndrome, Hutchinson–Gilford progeria syndrome and long QT syndrome. Whether more complex, sporadically occurring disease entities can be modelled with iPSCs remains uncertain.

  • Cell-based assays enable the discovery of novel pathways and the identification of compounds with favourable cell permeability and toxicity profiles, but such assays are less amenable to defining the structure–activity relationships that are important for optimizing drug properties.

  • iPSCs offer important advantages for drug toxicity screening against relevant human cells and tissues, and may facilitate the development of 'in vitro clinical trials' to test the efficacy of drugs or gene correction vectors against various distinct patient genotypes.

Abstract

The ability to generate induced pluripotent stem cells (iPSCs) from patients, and an increasingly refined capacity to differentiate these iPSCs into disease-relevant cell types, promises a new paradigm in drug development — one that positions human disease pathophysiology at the core of preclinical drug discovery. Disease models derived from iPSCs that manifest cellular disease phenotypes have been established for several monogenic diseases, but iPSCs can likewise be used for phenotype-based drug screens in complex diseases for which the underlying genetic mechanism is unknown. Here, we highlight recent advances as well as limitations in the use of iPSC technology for modelling a 'disease in a dish' and for testing compounds against human disease phenotypes in vitro. We discuss how iPSCs are being exploited to illuminate disease pathophysiology, identify novel drug targets and enhance the probability of clinical success of new drugs.

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Figure 1: An integrated model for drug discovery and development based on the iPSC technology platform.
Figure 2: Value creation with the iPSC-based drug discovery paradigm: comparison between conventional target-centric drug discovery and patient-derived iPSC-enabled drug discovery.
Figure 3: Schematic diagram of the iPSC-driven lead discovery platform based on iPierian's SMA programme.

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Acknowledgements

The authors would like to especially thank S. Irion, E. Vaisberg, I. Griswold-Prenner and C. Johnson for their crucial input and help with writing the manuscript. Special thanks to A. Rosenthal for his help in editing and integrating the manuscript, and M. Smith and B. Keon for their help with the graphic design.

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Author notes

  1. Marica Grskovic, Ashkan Javaherian and George Q. Daley: These authors contributed equally to this work.

Authors and Affiliations

  1. iPierian, 951 Gateway Blvd, South San Francisco, 94080, California, USA

    Marica Grskovic & Ashkan Javaherian

  2. Weizmann Institute of Science, Rehovot, 76100, Israel

    Berta Strulovici

  3. Division of Pediatric Haematology/Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Children's Hospital Boston and Dana Farber Cancer Institute,

    George Q. Daley

  4. Boston, 02115, Massachusetts, USA

    George Q. Daley

  5. Howard Hughes Medical Institute, Chevy Chase, 20815, Maryland, USA

    George Q. Daley

  6. Division of Hematology, Brigham and Women's Hospital,

    George Q. Daley

  7. Boston, 02115, Massachusetts, USA

    George Q. Daley

  8. Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    George Q. Daley

  9. Broad Institute of MIT and Harvard, Cambridge, 02142, Massachusetts, USA

    George Q. Daley

Authors
  1. Marica Grskovic
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  2. Ashkan Javaherian
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  4. George Q. Daley
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Corresponding author

Correspondence to George Q. Daley.

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Competing interests

Marica Grskovic and Ashkan Javaherian are both employed by iPierian, and Berta Strulovici is a former employee. George Q. Daley is on the scientific advisory board of iPierian. All co-authors hold equity in the company, which uses induced pluripotent stem cells to develop drugs against neurodegenerative diseases.

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FURTHER INFORMATION

George Q. Daley's homepage

Coriell Institute for Medical Research

Guidelines for Clinical Translation of Stem Cells

International Haplotype Mapping project

iPierian website

Johns Hopkins Clinical Compound Collections

MicroSource Spectrum Collection

Prestwick Collection

Sigma-Aldrich Library of Pharmacologically Active Compounds

UK Biobank

Glossary

Embryonic stem cells

(ESCs). Pluripotent cells derived from a pre-implantation-stage embryo. These cells are capable of dividing without differentiating for a prolonged period in culture.

Induced pluripotent stem cells

(iPSCs). Pluripotent cells derived from differentiated somatic cells through treatment with exogenous factors.

Disease phenotype

A molecular, cellular or functional manifestation of a disease in patient-derived cells.

Pluripotent stem cells

(PSCs). Undifferentiated cells that have the ability to self-renew and the potential to differentiate into cells of the three primary germ layers: endoderm, mesoderm or ectoderm.

Embryoid bodies

Aggregates of cells derived from pluripotent cells, formed by growing pluripotent cells in suspension in the absence of self-renewal-promoting factors. Following their aggregation, these cells differentiate into various differentiated cell types partly recapitulating early embryonic development.

Reprogramming

The process by which a differentiated somatic cell acquires the features of a pluripotent stem cell or a differentiated cell of a different cell type.

Spinal muscular atrophy

A monogenic neurodevelopmental disorder in which a reduced level of survival of motor neuron (SMN) protein leads to the degeneration of motor neurons during childhood.

Epigenetic

A heritable change in gene expression that is not caused by the DNA sequence.

Copy number variations

Duplications or deletions in the genome that lead to variability in the number of genes.

LEOPARD syndrome

An autosomal dominant multisystem disease caused by a mutation in the gene encoding protein tyrosine phosphatase non-receptor type 11. The disease affects the skin as well as the skeletal and cardiovascular systems.

QT interval

A measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart.

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Grskovic, M., Javaherian, A., Strulovici, B. et al. Induced pluripotent stem cells — opportunities for disease modelling and drug discovery. Nat Rev Drug Discov 10, 915–929 (2011). https://doi.org/10.1038/nrd3577

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